ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.5374_5375delinsAT (p.Ala1792Ile) (rs1131691296)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494037 SCV000581806 uncertain significance not provided 2020-12-01 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000554375 SCV000631786 uncertain significance Alstrom syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 8 of the ALMS1 mRNA (c.5377_5378delinsAT), replacing alanine with isoleucine at codon 1793 of the ALMS1 protein (p.Ala1793Ile). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 429278). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201217 SCV001372304 uncertain significance not specified 2020-06-15 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.5371_5372delinsAT (p.Ala1791Ile), also named as c.5377_5378delinsAT (p.Ala1793Ile) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found as a multinucleotide variant (2-73679028-GC-AT) at a frequency of 6.4e-05 in 280570 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (6.4e-05 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5371_5372delinsAT in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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